Novel 5-fluorouracil complexes of Zn(II) with pyridine-based ligands as potential anticancer agents

Abstract

A series of novel Zn(II) complexes of 5-fluorouracilate (5-FU), namely (Zn(5-FU)(2)(bpy)] (1), [Zn(5-FU)(2)(phen)] (2), [Zn(5-FU)(2)(dpya)]center dot H2O (3), [Zn(5-FU)(2)(bpyma)]center dot 2H(2)O (4) and [Zn(5-FU)(2)(terpy)]center dot H2O(5), were synthesized and structurally characterized by spectroscopic methods and X-ray crystallography. 5-FU was coordinated to Zn(II) via the deprotonated N3 site and also presented the N1 and N3 linkage isomerism in 4 and 5 due to its tautomerism. The antiproliferative activity of the complexes was studied against lung (A549), breast (MDA-MB-231), colon (HCT116) and prostate (DU145) cancer cell lines. Complexes 1, 4 and 5 except 2 and 3 showed potent growth inhibitory activity towards selected cancer cells. Remarkably, 4 was highly cytotoxic towards A549 and MDA-MB-231 cell lines, being more active than the clinical drugs cisplatin and 5-FU. In addition, 4 was not toxic to normal lung cells (BEAS-2B). The complex exhibited a significantly high affinity towards DNA as assessed by gel electrophoresis and DNA docking. The mechanistic studies of 4 in A549 cells indicated that the complex induced apoptotic cell death as evidenced via caspase 3/7 activity, Bcl2 inactivation, annexin V and DAPI/PI staining. 4 further elevated the levels of reactive oxygen species (ROS), depolarized mitochondria and enhanced the expression of gamma-H2AX, thus contributing to its remarkable anticancer activity.